Cervical cancer continues to threaten women’s health worldwide, and the incidence of cervical adenocarcinoma (AD) is rising in the developed countries. Previously, we showed that glucose-regulated protein 58 (Grp58) served as an independent factor predictive of poor prognosis of patients with cervical AD.
Liao et al BMC Cancer 2014, 14:555 http://www.biomedcentral.com/1471-2407/14/555 RESEARCH ARTICLE Open Access Glucose-regulated protein 58 modulates β-catenin protein stability in a cervical adenocarcinoma cell line Chia-Jung Liao1†, Tzu-I Wu1,2†, Ya-Hui Huang3, Ting-Chang Chang4, Chyong-Huey Lai4, Shih-Ming Jung5, Chuen Hsueh5,6 and Kwang-Huei Lin1* Abstract Background: Cervical cancer continues to threaten women’s health worldwide, and the incidence of cervical adenocarcinoma (AD) is rising in the developed countries Previously, we showed that glucose-regulated protein 58 (Grp58) served as an independent factor predictive of poor prognosis of patients with cervical AD However, the molecular mechanism underlying the involvement of Grp58 in cervical carcinogenesis is currently unknown Methods: DNA microarray and enrichment analysis were used to identify the pathways disrupted by knockdown of Grp58 expression Results: Among the pathway identified, the WNT signaling pathway was one of those that were significantly associated with knockdown of Grp58 expression in HeLa cells Our experiments showed that β-catenin, a critical effector of WNT signaling, was stabilized thereby accumulated in stable Grp58 knockdown cells Membrane localization of β-catenin was observed in Grp58 knockdown, but not control cells Using a transwell assay, we found that accumulated β-catenin induced by Grp58 knockdown or lithium chloride treatment inhibited the migration ability of HeLa cells Furthermore, an inverse expression pattern of Grp58 and β-catenin was observed in cervical tissues Conclusions: Our results demonstrate that β-catenin stability is negatively regulated by Grp58 in HeLa cells Overexpression of Grp58 may be responsible for the loss of or decrease in membranous β-catenin expression in cervical AD Background Cervical cancer is the third leading cause of cancerrelated mortality among women worldwide [1], although records show a marked decline in incidence over the past three decades Despite a reducing in the incidence of cervical squamous cell carcinoma (SCC), the frequency of cervical adenocarcinoma (AD) is increasing due to insufficient detection of cervical AD precursor lesions with the Papanicolaou smear test [2] Therefore, identification of biomarkers specific for cervical AD is essential for early detection and improved prognosis Persistent infection with high-risk human papillomavirus (HPV) is the major risk factor for both SCC and AD [3] * Correspondence: khlin@mail.cgu.edu.tw † Equal contributors Department of Biochemistry, Chang-Gung University, 259 Wen-hwa Road, Taoyuan 333, Taiwan Full list of author information is available at the end of the article However, HPV alone is not sufficient to cause cervical cancer; other molecular markers of cervical carcinogenesis are essential Previously, we demonstrated that glucoseregulated protein 58 (Grp58) serves as an independent prognostic factor for cervical AD, but not SCC [4] Cellbased studies revealed that Grp58 regulates the invasion and metastatic ability of HeLa cells Grp58 is a multifunctional protein belonging to the disulfide isomerase family of proteins [5] The functions of Grp58 in quality control of glycoprotein and major histocompatibility complex class I (MHC class I) maturation are well documented [6] Recent evidence has suggested that Grp58 plays a role in cancers [7,8], although the details are unclear In the current investigation, we explored the role of Grp58 in cervical AD progression and the molecular mechanism underlying Grp58 function © 2014 Liao et al.; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Liao et al BMC Cancer 2014, 14:555 http://www.biomedcentral.com/1471-2407/14/555 Methods Pathway enrichment analysis Pathway enrichment analysis of a set of differentially expressed genes upon Grp58 knockdown was performed using the GeneGo MetaCore analysis tool (GeneGo, St Joseph, MI) Genes displaying differential expression, by comparing stable control and Grp58 knockdown cells, greater than 1.2 fold were uploaded A pathway map with a false discovery rate of 1.2 and